Abstract 14985: Effects of Nerve Growth Factor on Processes Regulating Bone Marrow Progenitor Cells Mobilization after Myocardial Infarction
Mobilization of vascular progenitor cells (PCs) from the bone marrow (BM) requires activation of osteoclasts and proteases allowing for PCs detachment from the endosteal niche and egression into the circulation. We recently showed that the human infarcted heart presents higher expression of nerve growth factor (NGF) and that NGF gene transfer (GT) to the mouse peri-infarct myocardium improves vascular regeneration and cardiac function. Here, we investigated: 1) NGF as a chemoattractant of human BM-PCs; 2) the impact of acute myocardial infarction (aMI) and cardiac NGF GT on the mouse BM.
Human BM was obtained from patients either enrolled in a clinical trial with BM cell therapy of aMI or undergoing hip replacement surgery. BM mononuclear cells (MNCs) were prompted in migration assays to NGF. Moreover, FACS analysis for BM-derived PCs co-expressing the NGF TRKA receptor was performed on peripheral blood (PB) MNCs of aMI and healthy humans.
Furthermore, MI was induced by coronary ligation in mice. The mouse peri-infarct myocardium was infected (10^8 p.f.u. in 3 injections) with an adenovirus carrying human NGF (Ad.hNGF) or an empty vector control (Ad.Null). Sham-operated mice received Ad.Null.
BM-MNCs from patients with/out aMI migrated toward NGF (P<0.05 for both comparisons vs BSA). Additionally, human aMI increased the % of BM-derived circulating CD34+/c-kit+ PCs co-expressing TRKA (P<0.05 vs healthy controls).
In aMI mice, intra-cardiac Ad.hNGF induced the presence of hNGF in BM supernatant (ELISA assay). Immunohistochemical analyses on femurs and tibias showed that aMI increases the number of both TRAP+ activated osteoclasts lining the endosteal surface and MMP9+ BM stromal cells and that both responses were accelerated and amplified by cardiac NGF GT (P<0.05 vs MI/Ad.Null for both comparisons at 1 and 2d post-MI). Additionally, MI increased c-kit+/CD45- PCs in the BM parenchyma and this response was further potentiated by NGF GT (39.4±8 vs 26±4 cell/105 in MI/Ad.Null at 3d post-MI; p<0.05). Also, the % of BM c-kit+/Ki67+ proliferating cells was increased by NGF GT at 3d (P<0.05 vs MI/Ad.Null).
Taken together, our data suggest that cardiac NGF level contributes to regulate the post-MI mobilization of vascular PCs from the BM.
- © 2012 by American Heart Association, Inc.